Gene augmentation therapy successfully treats mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity

Abstract

Recombinant adeno-associated virus (rAAV) mediated gene therapy is an effective approach for targeting therapeutic genes to retinal photoreceptors. Complete congenital stationary night blindness (cCSNB) is a genetically heterogeneous inherited retinal disease caused by mutations in one of several genes that are part of a large, interdependent depolarizing bipolar cell (DBC) signalplex required for normal synaptic signaling with photoreceptors. These genes include NYX, GRM6, TRPM1, GPR179, and LRIT3, and the resulting cCSNB phenotype is characterized by abnormally low-light vision, myopia, and nystagmus, but does not include retinal degeneration. Because of the non-progressive and recessive nature of cCSNB, we investigated the potential of a gene augmentation approach in the mature retina to improve retinal function and cortical visual acuity. We used a mouse model of cCSNB caused by LRIT3 loss to evaluate the efficacy of a single subretinal injection of an rAAV expressing LRIT3 in either rods or cones, and the extent of restoration of retinal function and visual acuity. We show that gene augmentation by expressing LRIT3 in Lrit3–/– retinas of mature mice restores the DBC synaptic signaling complex and is sufficient to rescue retinal function and improve visual acuity.